Alpha-1-adrenergic receptors are G-protein coupled transmembrane receptors that mediate various actions of the sympathetic nervous system through the binding of the catecholamines, epinephrine, and norepinephrine (NE). Currently, several subtypes of the alpha-1 adrenergic receptors are known to exist for which the genes have been cloned: alpha-1A (previously known as alpha-1C), alpha-1B and alpha-1D.
Alpha-1 adrenoceptor antagonists have been shown in numerous clinical studies to be effective in relieving the symptoms associated with benign prostatic hypertrophy, also known as benign prostatic hyperplasia (BPH), an illness typically affecting men over fifty. The symptoms of the condition include, but are not limited to, increased difficulty in urination and sexual dysfunction. Drugs such as prazosin, indoramin, doxazosin and tamsulosin are in common clinical use for BPH, and are effective in reducing both “obstructive” symptoms (e.g. weak stream) and “irritative” symptoms (e.g. nocturia, urinary urge and frequency). However, these compounds are all non-subtype-selective and have the potential to cause significant side-effects, particularly cardiovascular effects such as postural hypotension, dizziness, and syncope, and CNS effects such as aesthenia (tiredness). These effects can limit dosing and the clinical efficacy in reducing symptoms associated with BPH.
Pharmacological studies resulting in the subdivision of alpha-1 adrenoceptors into alpha-1A, alpha-1B, and alpha-1D adrenoceptors have led to the suggestion that development of subtype-selective antagonists may allow for an improved symptomatic treatment of BPH with a lower incidence of dose-limiting side-effects. Recently, much interest has been focused on the role of the alpha-1A adrenoceptor subtype in BPH, as studies have shown that this subtype predominates in the urethra and prostate of man and appears to be the receptor mediating NE-induced smooth muscle contraction in these tissues. See, e.g., Price et al., J. Urol. (1993), 150, at 546–551; Faure et al., Life Sci. (1994), 54 at 1595–1605; Taniguchi et al., Naunyn Schmiedeberg's Arch. Pharmacol. (1997), 355 at 412–416, Forray et al., Mol. Pharmacol. (1994), 45 at 703–708; Hatano et al., Br. J. Pharmacol. (1994), 113 at 723–728; and Marshall et al., Br J. Pharmacol. (1995), 115, at 781–786. Smooth muscle tone is believed to contribute substantially to the total urinary outflow obstruction observed in patients with BPH [Furuya et al., J. Urol. (1982), 128 at 836–839]. Increased prostate mass is also a contributing factor. These observations have fuelled the hypothesis that an alpha-1A subtype-selective antagonist may, via a selective and significant decrease in outlet resistance, lead to improved pharmacotherapy for BPH.
However, in BPH, it is often the irritative symptoms which prompt the patient to seek treatment, and these irritative symptoms may be present in patients with no demonstrable obstruction (i.e. normal urine flow rates). Thus, it would be advantageous to provide a therapy for treating patients exhibiting obstructive symptoms and/or irritative symptoms. It is believed that reduction of obstructive and irritative symptoms in patients with BPH may be achieved via a combination of alpha-1A and alpha-1B subtype selectivity in a drug molecule. The lack of alpha-1D adrenoceptor antagonism is expected to lead to reduced or fewer side effects than those associated with the use of non-subtype-selective agents.
The instant invention provides arylamine-substituted quinazolinone compounds that are useful as alpha 1 a/b adrenergic receptor antagonists. Certain arylamine quinazoline compounds useful for other purposes are disclosed in Hess et al., Anti-hypertensive 2-Amino-4(3H)-quinazolinones, Medical Research Laboratories, Pfizer & Co. (January 1968); Klopman et al., Molecular Pharmacology, “An Artificial Intelligence Approach to the Study of the Structural Moieties Relevant to Drug-Receptor Interactions in Aldose Reductase Inhibitors,” Vol. 34, No. 6 (December 1988); DeRuiter et al., “Design and Synthesis of 2-(Arylamino)-4(3H)-quinazolinones as Novel Inhibitors of Rat Lens Aldose Reductase,” J. Med. Chem. Vol. 29 (1986), at pp. 627–29.
All publications, patents, and patent applications cited herein, whether supra or infra, are each hereby incorporated by reference in its entirety.